Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): a Review for Clinicians

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Endocrine-Related P W Rosario and NIFTP 26:5 R259–R266 Cancer G F Mourão REVIEW Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): a review for clinicians

Pedro Weslley Rosario and Gabriela Franco Mourão

Santa Casa de Belo Horizonte, Minas Gerais, Brazil

Correspondence should be addressed to P W Rosario: [email protected]

Abstract

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is Key Words an encapsulated or clearly delimited, noninvasive neoplasm with a follicular growth ff noninvasive follicular pattern and nuclear features of papillary thyroid carcinoma (PTC). It is considered a ‘pre- thyroid neoplasm malignant’ lesion of the RAS-like group. Ultrasonography (US), cytology and molecular ff follicular adenoma tests are useful to suspect thyroid nodules that correspond to NIFTP but there is wide ff papillary thyroid cancer overlap of the results with the encapsulated follicular variant of PTC (E-FVPTC). In these nodules that possibly or likely correspond to NIFTP, if surgery is indicated, lobectomy is favored over total thyroidectomy. The diagnosis of NIFTP is made after complete resection of the lesion by observing well-defined criteria. In the case of patients who received the diagnosis of FVPTC and whose pathology report does not show findings of malignancy (lymph node metastasis, extrathyroidal invasion, vascular/capsular invasion), if the tumor was encapsulated or well delimited, the slides can be revised by an experienced pathologist to determine whether the diagnostic criteria of NIFTP are met, but special attention must be paid to the adequate representativeness of the capsule and tumor. Since NIFTP is not ‘malignant’, tumor staging is not necessary and patients are not submitted to thyroid cancer protocols or guidelines. We believe that patients with NIFTP without associated malignancy and without nodules detected by US of the remnant lobe (if submitted to lobectomy) can be managed like those with follicular adenoma. Endocrine-Related Cancer (2019) 26, R259–R266

Definition The change from the noninvasive encapsulated follicular variant of PTC Noninvasive follicular thyroid neoplasm with papillary- (E-FVPTC) to NIFTP like nuclear features (NIFTP) is an encapsulated or clearly delimited, noninvasive neoplasm with a follicular When Nikiforov et al. (2016) proposed the term NIFTP, growth pattern and nuclear features of papillary thyroid it was already known that encapsulated/well-delimited carcinoma (PTC), but without well-formed papillae tumors of FVPTC without vascular/capsular invasion had or psammoma bodies and without typical findings of an excellent prognosis after complete resection, even when the aggressive subtypes of PTC or poorly differentiated treated only with lobectomy (Liu et al. 2006, Rivera et al. carcinoma (Nikiforov et al. 2016, 2018, Lloyd et al. 2017). 2010, Rosario et al. 2014, Ganly et al. 2015). In the largest It is considered a ‘borderline’ or ‘pre-malignant’ lesion series published so far (Rosario et al. 2014), we reported (Lloyd et al. 2017). no case of recurrence after 1–10 years (median 7 years)

-19-0048 Endocrine-Related P W Rosario and NIFTP 26:5 R260 Cancer G F Mourão of follow-up among 108 patients with this tumor, all of guidelines for differentiated thyroid carcinoma. Compared them >1 cm. None of the patients received radioiodine to data that include it as ‘malignant’ tumor, with NIFPT or TSH suppression and 57 were treated with lobectomy. no longer being considered ‘cancer’, a reduction in the risk Some guidelines already recommended more conservative of ‘malignancy’ is observed in thyroid nodules with the treatment for this histological subtype (Perros et al. 2014, features shown in Table 1, which are more frequently found Haugen et al. 2016). in lesions corresponding to NIFTP. This fact has possible Nevertheless, that publication (Nikiforov et al. implications for the predictive value for ‘malignancy’ of 2016) had a strong impact in clinical practice. First, the ultrasonography (US) (Chaigneau et al. 2018, Rosario et al. absence of metastases in 109 patients with tumors >1 cm 2018a,b), cytology (Cibas & Ali 2017, Rocha et al. 2018), treated without radioiodine and followed up for at least molecular tests (Sahli et al. 2017) and fluorodeoxyglucose 10 years reported in the multicenter study (Nikiforov positron emission tomography (FDG-PET) (Rosario et al. et al. 2016) reinforced the excellent prognosis of this 2019). Tumors that nowadays correspond to NIFTP were neoplasm after its complete resection. Second, removal of included in the group of low-risk PTC (Wong et al. 2017, the term ‘cancer’ itself probably (i) reduces the negative Rosario 2019a), that is, tumors restricted to the thyroid psychological impact on the patient and relatives; (ii) without vascular invasion or typical components of increases the physician’s safety to opt for conservative aggressive subtypes, in the absence of the BRAFV600E treatment and less intense follow-up and (iii) increases mutation (Haugen et al. 2016). Thus, a slight increase in patient acceptance of less aggressive therapy and less the recurrence rate may occur after the exclusion of NIFTP frequent follow-up. Third, clear diagnostic criteria were from this group. Clearly, all these impacts depend on the established since variations existed in the definition prevalence of NIFTP in the population studied and the of E-FVPTC. Indeed, this attempt to standardize the diagnosis of NIFTP is less often made in Asian populations diagnostic criteria, in which pathologists from several (Bychkov et al. 2018). countries participated, was an important contribution. Until then, different definitions, especially of the nuclear alterations sufficient to characterize PTC, resulted in a Preoperative suspicion of NIFTP significant interobserver variation in the final diagnosis of follicular thyroid neoplasms. A detailed review of this Although the preoperative diagnosis is not possible, aspect was recently published in this journal (Amendoeira knowledge of thyroid nodules that possibly or likely et al. 2018). Fourth and probably the most important, in correspond to NIFTP is important. In these nodules, if addition to the name change from noninvasive E-FVPTC surgery is indicated, lobectomy is recommended, except to NIFTP, the nature of the lesion was altered, which was if the choice for total thyroidectomy were due to reasons no longer classified as ‘malignant’. This proposal was other than the risk of malignancy of the nodule or to subsequently endorsed by the World Health Organization concern about another nodule. (WHO) in the 4th edition of the classification of endocrine Ultrasonography (Hahn et al. 2017, Rosario 2017a, tumors (Lloyd et al. 2017). Yang et al. 2017), cytology (Rosario 2017a, Bongiovanni Since NIFTP is not ‘cancer’, tumor staging (e.g., et al. 2018) and molecular tests (Nikiforov 2017) are TNM/AJCC) is not necessary and patients with this useful for suspecting NIFTP. Some results render NIFTP diagnosis do not need to be submitted to protocols or unlikely (Table 1) and are more characteristics of classical

Table 1 Data that lead to the reasonable possibility of a thyroid nodule corresponding to NIFTP.

Clinical examination Absence of clinically apparent or known metastasis of thyroid origina Ultrasonography Absence of LNMa Nodule without the following findings: extrathyroidal extension, microcalcification, taller-than-wide shape, spiculate/microlobulate/ill-defined margin, high suspicion of malignancy Fine-needle aspiration Category III, IV or V cytology of the Bethesda systemb Nodule without mutations or with RAS or other RAS-like mutations (e.g., PAX8/PPARG rearrangement)c aThe presence excludes NIFTP or indicates associated thyroid malignancy; bfollicular pattern, no papillae, no psammomatous calcifications, no florid nuclear features of papillary thyroid carcinoma, no necrosis or mitoses; cNIFTP is virtually excluded in the case of a nodule with BRAFV600E or other BRAFV600E-like mutations (e.g., RET/PTC fusions), or high-risk mutations (e.g., TERT promoter, p53).

PTC, infiltrative FV and aggressive subtypes. In contrast, but all 13 tumors had papillae. Lee et al. (2017) reported these tumors less frequently exhibit the typical findings the mutation in 5/24 cases. When four of these five cases of nodules that correspond to NIFTP (Table 1). However, were revised, papillae were found in one case, capsular the findings of NIFTP and E-FVPTC, especially with lower invasion in another and inadequate representativeness invasion, widely overlap. The Doppler vascularization of the tumor in the other two (Kakudo et al. 2018). In pattern (Hahn et al. 2017, Yang et al. 2017, Rosario 2018b), the series of Kim et al. (2018c), 9/73 NIFTP carried the histogram analysis of greyscale sonograms (Kwon et al. mutation: four tumors with well-formed papillae, four 2018) and uptake of FDG on PET (Rosario 2018d) have with abortive papillae and one result was false-positive been studied but do also not distinguish NIFTP from because of adjacent BRAF-positive PTC. Zhao et al. (2017) E-FVPTC. found 1/48 NIFTPs with the BRAFV600E mutation, but the authors recognize that the lack of examination of the entire tumor may have failed to detect the components of classical PTC. Diagnosis of NIFTP Despite the small number of reported cases, the At present, the diagnosis of NIFTP can only be made after diagnosis of NIFTP also applies to children and adolescents complete resection of the lesion observing the following and the absence of metastases has been demonstrated in criteria (Nikiforov et al. 2016, 2018, Lloyd et al. 2017): this age group (Chereau et al. 2019, Rosario & Mourão (i) encapsulation or clear demarcation from adjacent 2018). thyroid parenchyma; (ii) follicular growth pattern with The size of the tumor does not constitute a criterion no well-formed papillae, no psammoma bodies and <30% for the diagnosis of NIFTP (Nikiforov et al. 2018), although solid/trabecular/insular growth pattern; (iii) nuclear some cases require greater care and time-consuming features of PTC (nuclear score 2–3); (iv) no vascular or evaluation to ensure the absence of excluding findings. capsular invasion; (v) no tumor necrosis or high mitotic Reviewing 250 patients with subcentimeter NIFTP from activity. Molecular tests are helpful but not required for nine studies (Thompson 2016, Can et al. 2017, Hahn et al. NIFTP diagnosis. When obtained, BRAFV600E or other 2017, Kwon et al. 2017, Johnson & Sadow 2018, Mainthia BRAFV600E-like mutations (e.g., RET/PTC fusions) or et al. 2018, Rosario 2018c, Shafique et al. 2018, Xu et al. high-risk mutations (e.g., TERT promoter, p53) are absent 2018), without associated PTC, we found only two patients in NIFTP (Nikiforov et al. 2018). The initial criteria with micrometastases <2 mm in a single lymph node in the (Nikiforov et al. 2016) were revised in 2018 (Nikiforov central compartment, none with distant metastases and et al. 2018). In the presence of true well-formed papillae, no case of recurrence. In addition, reviewing 265 patients even if accounting for <1% of the tumor, the latter is no with NIFTP ≥4 cm (Thompson 2016, Golding et al. 2017, longer considered NIFTP (Nikiforov et al. 2018). Tumors Kwon et al. 2017, Rosario 2017b, Xu et al. 2017a, Chereau with papillae have been associated with a non-negligible et al. 2019, Kim et al. 2018b, Mainthia et al. 2018, Parente frequency of the V600E mutation in the BRAF gene (Cho et al. 2018), excluding cases with associated PTC, we did et al. 2017, Kim et al. 2018b,c, Rosario 2019b), lymph not identify any patients with lymph node metastases node metastases (Cho et al. 2017, Kim et al. 2018c, Rosario (LNM), only one with pulmonary metastases and no case 2019b), and even a case of distant metastasis (Cho et al. of recurrence. 2017). If exuberant nuclear alterations of PTC (score 3) Although there is no consensus, we believe that are present, comprehensive revision of the entire tumor tumors composed of cells with oncocytic (Hürthle cells) capsule interface is recommended in order to identify appearance can be classified as NIFTP if they meet all invasion and of the entire tumor in order to identify other diagnostic criteria (Xu et al. 2019). We report here structural components of PTC (Nikiforov et al. 2018). the evolution of ten patients with NIFTP with oncocytic When morphological criteria are strictly observed, features seen at our institution. There were eight women the finding of theBRAFV600E mutation in NIFTP is very and two men ranging in age from 18 to 72 years. unlikely and most studies show its absence (Nikiforov et al. Median tumor size was 2.2 cm (range, 1.1–3.5 cm). Six 2016, Johnson & Sadow 2018, Johnson et al. 2018, Jung patients were submitted to total thyroidectomy and et al. 2018, Kim et al. 2018a). We reviewed studies that four to lobectomy. No LNM were detected at diagnosis. reported exceptional cases of NIFTP with the BRAFV600E Complete resection of the primary tumor was achieved mutation. Cho et al. (2017) and Kim et al. (2018b) found in all patients. Radioiodine was not administered to any this mutation in 10/105 and 3/43 cases, respectively, of the ten patients. The patients were followed up for

18–144 months (median 72 months). None of the patients Table 2 lists the studies involving the largest number of developed structural disease or biochemical recurrence patients with NIFTP that reported ‘outcomes’. during follow-up. The presence of metastases in patients with NIFTP does not necessarily confirm its potential of dissemination. First, insufficient representativeness of the tumor and capsule that fails to detect findings excluding NIFTP Outcomes in studies involving patients cannot be ruled out in some retrospective studies. Second, with NIFTP the capacity of minute microcarcinomas (<3 mm) to Since a greater representativeness (capsule and tumor) metastasize to lymph nodes (Wada et al. 2003) and even to than usually obtained in the past is currently required distant organs (Xu et al. 2017b) is known. Many patients for the diagnosis of NIFTP, we do not believe that the with NIFTP could have these minute microcarcinomas frequency of ‘outcomes’ (i.e., metastases on presentation that were not detected by US of the remnant lobe (in and recurrences) reported in retrospective studies is patients submitted to lobectomy) or that escaped the underestimated (Rosario & Mourão 2019). On the contrary, slides obtained from the tumor. Another possibility would it is possible that they diagnosed retrospectively as NIFTP be regression of the microcarcinoma after it metastasized. tumors that were PTC; with the current requirement, The report of dissociation between LNM with mutation in even better results (in terms of ‘outcomes’) are expected the BRAF gene and the primary tumor (NIFTP) negative (Rosario & Mourão 2019). for this mutation supports the hypothesis of another, Reviewing studies published since the pioneering although not apparent, metastasis origin (Kim et al. article (Nikiforov et al. 2016) until December 2018 and 2018b). excluding patients with known associated PTC or tumors with well-formed papillae (in <1% of the tumor) that are no longer diagnosed as NIFTP (Nikiforov et al. 2018), we Management after resection found no report of death due to NIFTP and only one case of pulmonary metastasis (Parente et al. 2018). However, In patients with NIFTP, after its complete resection and LNM were reported (Jiang et al. 2016, Cho et al. 2017, in the absence of associated malignancy (including Hahn et al. 2017, Kwon et al. 2017, Kim et al. 2018b,c, microcarcinoma), the need for and protocol of follow-up Parente et al. 2018, You et al. 2018). Evaluation of these are matters of debate. There seems to be consensus that last cases showed that (i) involvement was restricted to suppression of TSH is not necessary. According to the the central compartment (N1a) in all patients, (ii) all American Thyroid Association, complementary tests but one patient had a single lymph node affected, (iii) (thyroglobulin (Tg), antithyroglobulin antibodies (TgAb), all but one study reported the size of LNM and all were neck US) are not mandatory (Haugen et al. 2016), while microscopic (<2 mm) and (iv) no recurrence was reported. some authors recommend NIFTP to be monitored in the

Table 2 Outcomes (metastases on presentation or recurrences) observed in studies involving the largest number of patients with NIFTP.

Reference Number of patients Length of follow-up LNM* Distant metastasis* Thompsom (2016) 77 1.2–12.5 years (median 11.8) 0 0 Nikiforov et al. (2016) 109 10–26 years (median 13) 0 0 Rosario et al. (2016) 129 12–146 months (median 72) 0 0 Xu et al. (2017a) 79 0.3–26 years (median 5.8) 0 0 Kwon et al. (2017) 105 – 2 0 Cho et al. (2017) 95 17–96 months (median 36) 2 0 Parente et al. (2018) 102 0–11 years (mean 5.7) 5 1 Mainthia et al. (2018) 164 IQR 12–49 months (median 24) 0 0 Johnson and Sadow (2018) 130 Mean 1.63 years 0 0 Chereau et al. (2019) 363 IQR 12–146 months (median 55) 0 0 Kim et al. (2018c) 73 0.6–31.9 months (mean 15.5) 2 0

*Diagnosed on presentation or during follow-up in patients with NIFTP according to the current criterion and without associated carcinoma. IQR interquartile range; LNM, lymph node metastases.

https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-19-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 07:55:22AM via free access Endocrine-Related P W Rosario and NIFTP 26:5 R263 Cancer G F Mourão same way as low-risk PTC (Cho et al. 2017, Parente et al. malignancy (LNM, extrathyroidal invasion, vascular/ 2018). capsular invasion) can have their slides revised by an After the name change removing the term ‘cancer’ experienced pathologist if the tumor is encapsulated or (Nikiforov et al. 2016), alteration of the nature of the well delimited (non-infiltrative) in order to determine lesion which is no longer ‘malignant’ (Lloyd et al. 2017), whether the diagnostic criteria of NIFTP are met. In and definition of somehow strict diagnostic criteria this reassessment, special attention must be paid to the designed exactly to rule out the possibility of metastases adequate representativeness of the capsule and tumor (Nikiforov et al. 2018), maintaining patients with NIFTP and establishment of the diagnosis of NIFTP is not under a similar follow-up as patients with PTC seems to recommended if it is insufficient unless more sections can be little justified Rosario( & Mourão 2019). In our view be submitted. The diagnosis of NIFTP cannot be based (Rosario 2018a, Rosario & Mourão 2019), if patients with on retrospective interpretation of the original pathology NIFTP continue to be followed up like those with low- report, especially when this report was obtained before risk PTC, the practical impact promoted by these changes definition of the current diagnostic criteria. would have been minimal or none since noninvasive Despite its inclusion in the WHO classification of E-FVPTC was known to have an excellent prognosis after endocrine tumors (Lloyd et al. 2017), it may still take some lobectomy (Liu et al. 2006, Rivera et al. 2010, Rosario et al. time until the NIFTP nomenclature becomes routine in all 2014, Ganly et al. 2015) and conservative treatment of pathology laboratories. During this period of transition, this histological subtype was already recommended by the we recommend revision by pathologist in the case of a available guidelines (Perros et al. 2014, Haugen et al. 2016). diagnosis of noninvasive E-FVPTC or FVPTC with the It is expected that specific protocols or characteristics cited above (neoplasm with capsule or recommendations for selective follow-up of subgroups clear delimitation without LNM, extrathyroidal invasion, of patients with NIFTP will be proposed, but they will capsular/vascular invasion) to determine whether the be empirical and based on the extrapolation of data tumor meets the criteria for NIFTP. from patients with ‘cancer’. Finally, because of the In the above situations, molecular tests can be exceptionality of ‘outcomes’, performing follow-up requested if available and feasible, but they do not similar to that of low-risk PTC to detect an ‘eventual’ substitute histology. recurrence of NIFTP would require hundreds of tests of Tg, TgAb and US at the end of 10 years, with probably unviable costs and numerous false-positive results and their potential consequences (Rosario et al. 2018c). Conclusion We believe that patients with NIFTP without Clinicians must be aware of the ultrasonographic, associated malignancy and without nodules detected cytological and molecular findings of nodules by US of the remnant lobe (if submitted to lobectomy) corresponding to NIFTP since this knowledge influences can be managed like those with follicular adenoma. This the definition of the extent of surgery, if indicated, favoring management seems to be more harmonic with the current lobectomy. In addition, clinicians and pathologists must nomenclature (not containing the term ‘cancer’) and the be familiar with the histological criteria for the diagnosis nature of the lesion (not ‘malignant’) and is based on (i) the of NIFTP to spare patients with this tumor (without existence of well-defined diagnostic criteria, (ii) molecular associated malignancy) from additional treatment signature, (iii) rarity of metastases on presentation, a and from the traditional follow-up recommended for finding that can even be a coincidence and (iv) the virtual differentiated thyroid cancer. absence of recurrences. These last aspects have been demonstrated in the past for noninvasive E-FVPTC and now using the criteria of NIFTP. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Revision of histology slides Funding Patients who were diagnosed in the past with FVPTC This research did not receive any specific grant from any funding agency in and whose pathology report did not show findings of the public, commercial or not-for-profit sector.

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Received in final form 21 February 2019 Accepted 7 March 2019